A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

Cellular and Molecular Life Sciences - Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations...     

Evaluation and control of miRNA-like off-target repression for RNA interference

RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.     

Intrinsic forces alone are sufficient to cause closure of the neural tube in the chick

Summary An isolated neural plate or a postnodal piece of early chick embryos, when cultured under appropriate experimental conditions, can undergo morphogenetic movements and form tubular structures closely resembling neural tubes of early chick embryos.This work was supported by grants from the NIH (NS 23200 and NS 21730) and the Busch Fund of Rutgers University.     

Comparison of classifications using measures intermediate between metric dissimilarity and consensus similarity

Two fundamental approaches to the comparison of classifications (e g, partitions on the same finite set of objects) can be distinguished One approach is based upon measures of metric dissimilarity while the other is based upon measures of similarity, or consensus These approaches are not necessarily simple complements of each other Instead, each captures different, limited views of comparison of two classifications The properties of these measures are clarified by their relationships to Day's complexity models and to association measures of numerical taxonomy The two approaches to comparison are equated with the use of separation and minimum value sensitive measures, suggesting the potential application of an intermediate sensitive measure to the problem of comparison of classifications Such a measure is a linear combination of separation sensitive and minimum value sensitive components The application of these intermediate measures is contrasted with the two extremes The intermediate measure for the comparison of classifications is applied to a problem of character weighting arising in the analysis of Australian stream basinsWe thank Bill Day, Mike Austin, Peter Minchin and two anonymous referees for many helpful comments We also thank P Arabie for useful discussion of consensus methods and character weighting     

Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

Cutting the axons of the cholinergic neurons that project to the hippocampal formation results in death of most of these cells. Previous studies have shown that administration of nerve growth factor before or at the same time as the lesion will prevent this cell death. Here we demonstrate that basic fibroblast growth factor (FGF) administered into the brain reduces the death of cholinergic neurons in the medial septum and diagonal band of Broca after transection of their axons, in both young adult and aged rats. Moreover, FGF can partially protect against death of cholinergic neurons even when administered two days after axonal transection. These results indicate a possible function for FGF in the normal support of basal forebrain cholinergic neurons, but its range of activity could be wider, for FGF also supports noncholinergic neurons in vitro, it is localized in many of the central nervous system neurons, and it is found in relatively high concentrations in the brain.     

The effects of acute and chronic morphine on regional distribution of cardiac output in brain

Both acute and chronic administration of morphine resulted in an increase in the percent cardiac output received by brain. However, various brain regions were affected differently by the drug treatments. The greatest increases in percent cardiac output received after chronic administration of morphine occurred in pons and cerebellum, while the greatest increases after acute administration occurred in cortex and midbrain. The changes found are in contrast with earlier studies which suggest that morphine has no effect on cerebral blood flow.     

Population coding of saccadic eye movements by neurons in the superior colliculus

The deeper layers of the superior colliculus are involved in the initiation and execution of saccadic (high velocity) eye movements. A large population of coarsely tuned collicular neurons is active before each saccade. The mechanisms by which the signals that precisely control the direction and amplitude of a saccade are extracted from the activity of the population are unknown. It has been assumed that the exact trajectory of a saccade is determined by the activity of the entire population and that information is not extracted from only the most active cells in the population at a subsequent stage of neural processing. The trajectory of a saccade could be based on vector summation of the movement tendencies provided by each member of the population of active neurons or be determined by a weighted average of the vector contributions of each neuron in the active population. Here we present the results of experiments in which a small subset of the active population was reversibly deactivated with lidocaine. These results are consistent with the predictions of the latter population-averaging hypothesis and support the general idea that the direction, amplitude and velocity of saccadic eye movements are based on the responses of the entire population of cells active before a saccadic eye movement.     

Extraneuronal serotonin accumulation in peripheral arteries of the rat

Accumulations of serotonin (5-HT) and norepinephrine (NE) were compared in control and 6-hydroxydopamine (6-OHDA) pretreated rat aorta, mesenteric and tail arteries. The distribution of these amines was corrected by subtracting tissue uptake of tritiated sorbitol in the extracellular space. 5-HT greatly accumulated both in control and 6-OHDA pretreated arteries. In contrast, NE accumulation in mesenteric and tail arteries was substantially decreased after 6-OHDA treatment. In the aorta 6-OHDA pretreatment did not affect the accumulation of both amines. These findings suggest that 5-HT accumulation in these arteries is mainly extraneuronal, and NE mainly neuronal. Since the accumulation of 5-HT in the aorta was not influenced by pretreatment with 10 microM NE, the extraneuronal uptake mechanisms for 5-HT and NE appear to be different.     

Variety Membership Problem for Two Classes of Non-Finitely Based Semigroups

The variety membership problem for two classes of non-finitely based semigroups is considered. It is shown that a finite semigroup S belongs to the variety generated by one of these non-finitely based semigroups if and only if S satisfies four certain equations that involve at most 2│S│+1 distinct variables.     

Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes.

Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.